Lipedema is a disorder characterized by massive, bilateral accumulation of fat below the waist and in the legs. Enlargement of the lower extremities is often accompanied by leg pain and accumulation of fluid. Little is known about the functional changes that lead to fat accumulation and pain in women with lipedema. The goals of this project are to conduct a comprehensive characterization of abdominal and femoral fat tissues in lean and obese women with lipedema and to evaluate the potential effect of diet-induced weight loss as a therapy.

Once enrolled in the study, the following tests will be conducted on lean women with lipedema: characterization of body composition (fat tissue distribution), insulin sensitivity (response to insulin) and adipose tissue biology. The following tests will be conducted on obese women with lipedema: characterization of body composition (fat tissue distribution), insulin sensitivity (response to insulin), adipose tissue biology, and immune system function/inflammation. As control groups, we will compare body composition and insulin sensitivity to: i) women with obesity without lipedema who are matched on age, body mass index, total body fat mass, and percent body weight as fat; and ii) women who were lean and healthy to serve as a normal comparator for the 2 groups with obesity. Participants in the 2 control groups will enroll in a different study at Washington University (IRB# 201512086) where the same procedures will be performed to assess body composition and insulin sensitivity.

A second aim of the study is to determine the effect of diet-induced weight loss on body composition, insulin sensitivity, and adipose tissue biology in women with lipedema. The results from this second aim of the study will provide important insights on the efficacy of diet therapy in managing lipedema.

Once informed consent has been obtained, participants will complete a screening visit that will include a medical history, physical examination, pregnancy test (for women of childbearing potential), blood tests, urine drug test, an oral glucose tolerance test, resting electrocardiogram (ECG), and questionnaires.

Baseline testing will be performed over 2 visits requiring 1 inpatient overnight stay and will require approximately 30 hours in total to complete testing. Testing will include magnetic resonance imaging scans to determine thigh fat mass; abdominal (belly) fat mass and liver fat content; DXA scan to assess whole-body and leg fat mass; blood samples; hyperinsulinemic-euglycemic clamp procedure to assess insulin sensitivity; immune system function/inflammation (performed exclusively in people with obesity and lipedema and BMI-matched controls); and adipose tissue (fat) biopsies.

Once Baseline Testing is completed, participants will start 5-10% dietitian and/or behaviorist guided weight-loss for about 4 to 6 months.

Participant will keep a food diary and have weekly visits (in person or remote) with a study dietitian and/or behaviorist.

After weight loss, the testing completed during baseline will be repeated.

Study procedures:

1. Medical history & physical exam
2. Urine drug/pregnancy Test
3. Blood pressure, pulse, height, weight
4. Electrocardiogram (ECG)
5. Blood tests for routine lab analyses
6. Oral glucose tolerance test (OGTT)
7. Screening Questionnaires
8. Dual energy X-ray absorptiometry (DXA) scan to assess whole-body and leg fat mass
9. Magnetic Resonance Imaging (MRI) to determine the amount of fat in the liver, abdomen (belly), and thigh.
10. Metabolism study (hyperinsulinemic-euglycemic clamp procedure) to assess how well insulin works to control blood glucose (sugar) concentrations.
11. Abdominal (belly) and thigh fat biopsies (women with obesity only)
12. Immune function (performed in people with obesity and lipedema only).

Inclusion Criteria:

• Diagnosis of Lipedema
• Lean women with lipedema (BMI >19.5 kg/m² and <26.0 kg/m²)
• Women with obesity and lipedema (BMI >30.0 kg/m² and <50.0 kg/m²)

Exclusion Criteria:

• Medical, surgical or biological menopause
• Previous bariatric surgery
• Diagnosis of Type 2 Diabetes
• HbA1C <5.7%
• Structured exercise >2 days/week for ≥35 minutes of intense exercise (e.g., jogging, activity that cause heavy breathing and sweating) or ≥150 minutes per week of structured exercise (e.g., brisk walking)
• Unstable weight (>4% change in weight during the last 2 months before entering the study)
• Significant organ system dysfunction (e.g., diabetes, severe pulmonary, kidney or cardiovascular disease)
• Cancer or cancer that has been in remission for <5 years
• Polycystic Ovary Syndrome
• Major psychiatric illness
• Conditions that render participant unable to complete all testing procedures (e.g., severe ambulatory impairments, limb amputations, or metal implants that interfere with imaging procedures; coagulation disorders)
• Use of medications that are known to affect the study outcome measures (e.g., steroids, non-statin lipid-lowering medications) or increase the risk of study procedures (e.g., anticoagulants) and that cannot be temporarily discontinued for this study
• Smoke cigarettes >10 cigarettes/week
• Consume >14 units of alcohol per week
• Pregnant or lactating women
• Persons who are not able to grant voluntary informed consent
• Persons who are unable or unwilling to follow the study protocol or who, for any reason, the research team considers not an appropriate candidate for this study, including non-compliance with screening appointments or study visits.

Adipose tissue RNA sequencing will be uploaded to Gene Expression Omnibus (GEO).

Before publication of manuscript containing RNA sequencing results

RNA sequencing results will be publicly available.